title: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
abstract: Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.
authors.affiliation: Centre of Excellence in Neuromics of Université de Montréal, Sainte-Justine Hospital Research Centre, Montréal, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.forename: Da-Ting
authors.initials: DT
authors.lastname: Lin
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Yoshizawa
authors.forename: Kyohei
authors.initials: K
authors.lastname: Higashi
authors.forename: A-Reum
authors.initials: AR
authors.lastname: Park
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: Amélie
authors.initials: A
authors.lastname: Piton
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tomitori
authors.forename: Hussein
authors.initials: H
authors.lastname: Daoud
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.forename: Edouard
authors.initials: E
authors.lastname: Henrion
authors.forename: Ousmane
authors.initials: O
authors.lastname: Diallo
authors.forename: Masoud
authors.initials: M
authors.lastname: Shekarabi
authors.forename: Claude
authors.initials: C
authors.lastname: Marineau
authors.forename: Michael
authors.initials: M
authors.lastname: Shevell
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.forename: Grant
authors.initials: G
authors.lastname: Mitchell
authors.forename: Amélie
authors.initials: A
authors.lastname: Nadeau
authors.forename: Guy
authors.initials: G
authors.lastname: D'Anjou
authors.forename: Michel
authors.initials: M
authors.lastname: Vanasse
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Lafrenière
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.forename: Jae-Ran
authors.initials: JR
authors.lastname: Lee
authors.forename: Kazuei
authors.initials: K
authors.lastname: Igarashi
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D016547:Kinesins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D012326:RNA Splicing / Q000235:genetics; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D013577:Syndrome
chemical_list: D015220:Calcium Channels; D003598:Cytoskeletal Proteins; D018698:Glutamic Acid; D016547:Kinesins; D008565:Membrane Proteins; D009479:Neuropeptides; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C491911:Cacng2 protein, rat; C490575:Kif1a protein, rat; C120557:erythrocyte membrane protein band 4.1-like 1